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Genetic association of non-MHC region with ankylosing spondylitis in a Chinese population
  1. Jing Liu1,2,
  2. Weilin Pu1,2,
  3. Yuan Li1,2,
  4. Yanyun Ma2,3,
  5. Qi Zhu4,
  6. Wei Wan5,
  7. Chengde Yang6,
  8. Xiaofeng Wang1,2,
  9. Xingdong Chen1,7,
  10. Xiaodong Zhou8,
  11. John D Reveille8,
  12. Li Jin1,2,
  13. Hejian Zou9,10,
  14. Jiucun Wang1,11
  1. 1 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
  2. 2 Human Phenome Institute, Fudan University, Shanghai, China
  3. 3 Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China
  4. 4 Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Guanghua Integrative Medicine Hospital, Shanghai, China
  5. 5 Division of Rheumatology and Immunology, Changhai Hospital, Shanghai, China
  6. 6 Division of Rheumatology, Ruijin Hosptial, Shanghai Jiaotong University Schools of Medicine, Shanghai, China
  7. 7 Fudan-Taizhou Institute of Health Sciences, Taizhou, China
  8. 8 Division of Rheumatology and Clinical Immunogenetics, The University of Texas-McGovern Medical School, Houston, TX, United States
  9. 9 Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China
  10. 10 Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China
  11. 11 Division of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
  1. Correspondence to Professor Jiucun Wang, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Division of Dermatology, Huashan Hospital, Shanghai 200438, China; jcwang{at}fudan.edu.cn; Hejian Zou, Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; hjzou{at}fudan.edu.cn

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Ankylosing spondylitis (AS) is a chronic inflammatory disease mainly affecting the sacroiliac joints and spine.1 In order to examine overall genetic susceptibility of AS, several genome-wide association studies (GWASs) were performed in Caucasian populations, and a number of genetic polymorphisms in non-major histocompatibility complex (MHC) regions were found, such as ERAP1, IL23R as well as many others.2–6 However, only a small portion of the single nucleotide polymorphisms (SNPs) were validated in East Asian (EA) populations.2 In recent years, multiple studies indicated significant genetic differences between different European and EA populations.2 7 To resolve this further, we have examined all reported AS-associated SNPs in non-MHC regions in Chinese patients with AS. A total of 1289 patients with AS and 1536 controls were included in this analysis, which have not been included in prior analyses.2 7 The sociodemographic and clinical characteristics of the cohort are presented in online supplementary table S1.

In this study, the candidate SNPs were mainly selected from six GWAS studies published from 2007 to 2016.2–6 8 Overall, 69 SNPs in non-MHC regions were included, 32 of which had not been validated in EA population before. The results of six loci (rs6759298, rs2297518, rs75301646, rs12615545, rs5837881 and rs27044) were consistent with prior reports in the Caucasian populations (table 1). Among them, the SNP rs2297518 in the NOS2 gene (OR/p_value (false discovery rate (FDR))=1.328/8.6E-03) and rs5837881 in an intergenic region (OR/p_value (FDR)=0.80/0.04) were not validated previously in EA populations, whereas four other SNPs were consistent with previous reports in Asian cohorts.2 7 Nine loci that had been previously associated with AS in relatively small cohorts of Chinese population were not validated in the present results (online supplementary table S2). Twenty-four loci that previously showed an association with AS but with p value not at genome-wide significance (>10−8) in both Caucasian and EA populations were not validated in our results (online supplementary table S3). Thirty-one loci previously reported implicated only in Caucasians did not show an association with AS in this study (online supplementary table S4).

In this study, all six SNPs showed significant differentiation between AS and controls in both Caucasians and our samples. Among them, rs6759298 located in a ‘gene desert’ at chromosome 2p15 showed highest significance in both Caucasian and Chinese data (OR/p value=1.31/3.60E-41, 1.22/3.81E-04, respectively). The Genotype-Tissue Expression dataset showed that rs6759298 has expression quantitative trait loci (eQTL) with B3GNT2 (online supplementary figure 1A). In addition, the database of Mouse Genome Informatics (MGI) showed that mice with B3gnt2-knocked-out showed increased levels of inflammatory cytokines such as interleukin (IL)-6, IL-1β and tumour necrosis factor-alpha). An association with another SNP (rs2297518) located in NOS2, which has never been reported in Chinese data of patients with AS, was found. It is a mutation that causes deleterious alterations in the coding region of NOS2. Rs75301646 is an intron variant on SULT1A2, which has eQTL with SULT1A1 expression (online supplementary figure 1B). MGI showed Sult1c1-knockout- mice have abnormal immune responses and increased sacral vertebrae number. Rs12615545 is near UBE2E3 and has eQTL with UBE2E3 (ubiquitin enzyme) in oesophageal mucosa, suggesting it might be related to inflammation status (online supplementary figure S1C).

Other loci were not validated in our samples such as IL12B, ANTXR2 and FCGR2A.9 We postulated that some different SNPs located in the same genes or genes in the same pathway can substitute for those loci in the Chinese population as has been observed with IL23R.2 Therefore, it is essential to find associated SNPs in different cohorts by sequencing or different chip analyses to extend our knowledge to the pathogenesis of AS.

Table 1

Genetic associations with AS and controls in the Chinese population

In conclusion, we genotyped 69 previously reported non-MHC AS-associated SNPs in a different Chinese cohort and found that six loci showed significant differences between patients with AS and controls in both Caucasian and EA populations. Usually, several SNPs may have similar effect to the same gene. Therefore, in the future, we can perform functional study of genes controlled by several SNPs in the mouse.

References

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Footnotes

  • JL and WP contributed equally.

  • Handling editor Josef S Smolen

  • Contributors JW and HZ designed the project and wrote the manuscript. JL and WP collected data, performed genotyping and analysis and wrote the manuscript. YL and YM managed all samples. QZ, WW and CY provided the ankylosing spondylitis samples. XW and XC provided the control samples. XZ, JDR and LJ revised the manuscript and provided valuable suggestions.

  • Funding The study was supported by research grants from the National Basic Research Program (2014CB541801), National Natural Science Foundation of China (31521003), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), International S&T Cooperation Program of China (2013DFA30870), 111 Project (B13016) and US NIH NIAID U01 (1U01AI090909) and China Medical Foundation. Computational support was provided by theHigh-End Computing Center located at Fudan University.

  • Competing interests None declared

  • Patient consent for publication Obtained.

  • Ethics approval Fudan University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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